Timothy O'Shea, PharmD, is a Clinical Pharmacist at Horizon Blue Cross Blue Shield of New Jersey. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency at Horizon. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.

Congestive heart failure (CHF) affects an estimated 5.7 million individuals in the United States and costs the nation over $30 billion each year.

In the 1980s, CHF meant a poor prognosis due to limited treatment options; annual mortality exceeded 50% and one-third of all CHF patients were hospitalized each year. With the advent of new treatment options, CHF mortality has decreased, yet still about half of those who develop heart failure die within 5 years of diagnosis.

Over the years, a number of landmark clinical studies on CHF have been published, shaping how we treat the disease today. Here are 6 of those that every pharmacist should know:

1. V-HeFT I (1986)1,2
This study marked one of the very first clinical studies in the CHF space. Prior to V-HeFT I, vasodilator therapy was commonly used in individuals with symptomatic heart failure; however, the effect on mortality hadn’t been quantified. Notably, beta blockers and ACE-inhibitors weren’t yet standard of care when the study was conducted.

Researchers enrolled 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive placebo, prazosin, or the combination of hydralazine and isosorbide dinitrate.

After an average follow-up of 2.3 years, all-cause mortality was lower in the combination group compared to the prazosin or placebo group (38.7% vs 49.7% vs 44.0%); however, the difference didn’t reach statistical significance. In a separate study published in 2004, A-HeFT, a statistically significant benefit in improving survival and reducing hospitalization was seen with isosorbide dinitrate/hydralazine among black patients.

Conclusion
A combination of isosorbide dinitrate and hydralazine showed a trend toward improved survival among those with CHF. In a later analysis, the combination was shown to reach statistical significance in black patients.

2. CONSENSUS (1987)3
The first ACE-inhibitor, captopril, was approved by the FDA in 1981 for hypertension; enalapril, another ACE-inhibitor would be approved 4 years later. CONCENSUS was conducted to understand the role ACE-inhibitors play in the treatment of CHF.

To answer this question, researchers assigned 253 patients in a double-blind study to receive either placebo or enalapril. Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Individuals were only included with NYHA class IV heart failure with a reduced ejection fraction (HFrEF). Follow-up averaged 188 days.

The study showed that at 6 months, the primary endpoint (overall mortality) was 40% lower in the enalapril group compared to placebo. Secondary endpoints of 12-month mortality and total mortality also demonstrated statistically significant reductions.

Conclusion
In patients with severe CHF, enalapril improves mortality and is well tolerated.

3. V-HeFT II (1991)4
To better define the efficacy of vasodilator therapy in the treatment of CHF, researchers compared the effects of hydralazine and isosorbide dinitrate with those of enalapril.

A total of 804 men receiving digoxin and diuretic therapy were enrolled in the study from 13 participating Veterans Affairs medical centers. Patients were randomized to receive either enalapril or hydralazine plus isosorbide dinitrate. Average follow-up time for the trial was 2.5 years.

At 2 years, mortality was significantly lower in the enalapril arm than in the hydralazine/isosorbide dinitrate arm (18% vs 25%). Over the course of the entire study, all-cause mortality rate remained lower with enalapril (33% vs 38%), however, this difference no longer reached statistical significance. There were no significant differences between the 2 groups in the rates of hospitalization for heart failure.

Conclusion
ACE inhibitor therapy was shown to be superior to the combination of hydralazine and isosorbide dinitrate at 2 years; however, the difference didn’t reach statistical significance over the entire course of the study

4. SOLVD (1991)5
Due to positive results from CONSENSUS, investigators sought to examine the effects of ACE-inhibitors on a broader range of HF patients.

In this study, 2569 patients receiving conventional treatment for heart failure and with a left ventricular ejection fraction (LVEF) 35% or less were randomly assigned in a 1:1 ratio to receive either placebo or enalapril. Approximately 90% of the patients were in NYHA functional classes II and III. The follow-up averaged 41.4 months.

At the conclusion of the study, there were 510 deaths in the placebo group, as compared with 452 in the enalapril group, a statistically and clinically significant reduction of 16%. Additionally, there was a 26% reduction in the enalapril group in the combined endpoint of death or hospitalization for CHF. The authors estimated that treating 1000 CHF patients with enalapril for about 3 years would prevent 50 premature deaths and an additional 350 hospitalizations.

The results from both CONSENSUS and SOLVD resulted in ACE-inhibitors quickly becoming standard of care in HFrEF patients.

Conclusion
Enalapril reduces mortality and HF hospitalizations when added to conventional therapy in patients with HFrEF.

5. DIG (1997)6
By the close of the 20th century, digoxin had become one of the most commonly prescribed medications for heart failure. Despite this, there was considerable controversy among experts regarding its long-term efficacy and safety.

To determine its impact on survival and hospitalization for heart failure researchers conducted a randomized, double-blind, placebo-controlled trial. In the study, 6800 patients with LVEF 45% or less, and who were taking diuretics and ACE-inhibitors, were randomly assigned to digoxin or placebo. The average follow-up was 37 months.

After analysis of the data, mortality was unaffected (35% in both groups). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure; however, it didn’t reach statistical significance. Digoxin reduced the total number of hospitalizations by 28%.

6. RALES (1999)7
Around the time of the study’s publication, aldosterone had been identified as playing an important role in the pathophysiology of HF. However, many physicians assumed that aldosterone formation would be adequately inhibited by ACE-inhibitors. Moreover, spironolactone, an aldosterone-receptor blocker, was infrequently used during this time due to a lack of evidence and because it was relatively contraindicated with ACE-inhibitors due to the risk of serious hyperkalemia.

In a double blind study, 1663 patients with severe heart failure and a LVEF less than 35% were randomized to receive either spironolactone or placebo daily. At baseline, patients were being treated with an ACE-inhibitor, a loop diuretic, and in most cases digoxin.

After a mean follow-up period of 24 months, the trial was discontinued early. Compared with the placebo group, there was a 30% reduction in all-cause mortality with spironolactone. The frequency of hospitalization for worsening heart failure was 35% lower in the spironolactone group than with placebo. The incidence of serious hyperkalemia was minimal in both groups.

Conclusion
In patients with HFrEF, spironolactone led to a reduction in all-cause mortality.